(A) Field of the Invention
This invention relates to the preparation of aqueous dispersions of water-swellable polymer particles and to the particles obtained from such a process.
(B) Description of the Prior Art
Aqueous dispersions of water-soluble polymer particles are difficult to manufacture. It is particularly difficult to control particle size and shape and to make such particles reproducibly. Aqueous dispersions of water-soluble polymer particles that have been available prior to this invention are, in general, not satisfactory. Previously, such particles are generally prepared by adding a crosslinking agent to an aqueous polymer solution under agitation. Agitation serves to break down the crosslinking polymer to give the desired particle size. To break down the crosslinked and crosslinking polymers, sufficient mechanical stress to cause shearing and disruption of particle integrity is required. This level of mechanical stress can only be achieved by applying vigorous agitation. This concurrent agitation-crosslinking method gives an undesirably broad distribution of particle sizes and shapes, and produces undesirable particle fragments. Additionally, there is substantial variability in the resulting particle populations between production runs.
A particularly undesirable aspect of the heterogeneous particle population produced by this method is that it is difficult or impossible to "clean up" or fractionate the heterogeneous population to yield a homogeneous population of particles having the same size and shape. A homogeneous population of particles is particularly desirable where the particles are to be delivered by injection through a narrow gauge syringe needle.
Other processes for preparing aqueous dispersions of crosslinked water-soluble polymer particles involve methods that are of a proprietary nature. However, such particles are either not available in the quantities to meet commercial demand, their physical parameters are not suitable for a particular application, or their properties cannot be varied systematically. Moreover, a full range of polymer compositions and sizes has not been available.
Water-soluble particles have various utilities. There are three basic types of water-based polymers:
(a) Solution Polymers
These polymers comprise dispersions of individual polymer molecules. The viscosity of the solution depends upon the molecular weight and concentration of the polymer; the higher the molecular weight and concentration, the higher is the viscosity of the solution. The viscosity of the solution limits the use of these solution polymers to low molecular weights and low concentrations. This is especially true where the use involves delivery of particles via injection through a narrow gauge syringe needle.
(b) Latexes
These polymers comprise colloidal dispersions of polymer particles, each of which comprises hundreds or thousands of polymer molecules. The viscosity of the latex depends upon the interactions between the colloidal particles and is independent of the molecular weight of the polymer. Thus, latexes often combine low viscosities with high polymer concentrations. Moreover, the mechanism and kinetics of emulsion polymerization favor the preparation of high-molecular-weight polymers with rapid rates of polymerization. Aqueous dispersions of crosslinked water-soluble polymers can be prepared by inverse emulsion or inverse suspension polymerization of monomer mixtures containing a crosslinking monomer, e.g., a mixture of acrylamide and methylene-bis-acrylamide. However, this method is limited to polymers that can be prepared by radical chain polymerization, which excludes natural water-soluble polymers. There remains a need to prepare particles of water-soluble polymers that are derived from natural sources.
(c) Water-Reducible or Water-Dispersible Polymers
These polymers have a degree of dispersion intermediate between that of solution polymers and that of latexes. The viscosity of these intermediate samples depends upon the relative degrees of solution polymer and latex polymer character. As with the latexes, this method is limited to polymers that can be prepared by radical chain polymerization.
Polysaccharides are naturally occurring biopolymers that exist in a highly viscous liquid state in animal tissues, where they readily react with proteins to from glycosaminoglycans or proteoglycans.
Biocompatible and non-biodegradable particles that are non-cytotoxic, non-carcinogenic, non-inflammatory, non-pyrogenic, and non-immunogenic are needed to provide a solution to the long felt and unfulfilled need for an improved composition useful for implants; soft tissue augmentation to treat congenital abnormalities, acquired defects, and cosmetic defects; and tissue scaffolding to promote cell growth.
Homogeneous populations of such particles would be particularly useful for soft tissue augmentation by surgical implantation or, preferably, delivery to the desired site by conventional injection through a narrow gauge syringe needle.
It would be particularly desirable to use such particles to treat urinary incontinence and vesicoureteral reflux, for correction of wrinkles and other skin defects, or to serve as a general augmention or replacement composition or as a scaffold material in soft or hard tissues such as breast, lip, penis, bone, cartilage, and tendon.
U.S. Pat. No. 4,124,705 to Rothman, et al. (hereinafter "Rothman") discloses hydrophilic, water-insoluble particles having a particle size between 0.1 and 300 micrometers which are composed of a polysaccharide or polysaccharide derivative such as starch, glycogen, or dextrins. The particles are crosslinked into a three-dimensional network by .alpha.(1.fwdarw.4)glucosidic linkages. This network is degraded in the body through hydrolyzation of the .alpha.(1.fwdarw.4)glucosidic linkages by .alpha.-amylase to form water-soluble fragments.
The Rothman particles are produced by bead polymerization in which a solution of the polysaccharide is dispersed to droplet form in an inert liquid, such as octanol, which may contain an emulsion stabilizer, such as Gafac.RTM. PE 510. A crosslinking agent, for example, a di- or multi-epoxides or a dicarboxylic acid, is then added to the reaction mixture. The octanol used in the Rothman process is a polar solvent which is miscible with the aqueous solution of the polysaccharide.
The Rothman particles are administered intravascularly in aqueous solutions, such as glucose, sorbitol, or saccharose, to block the finer blood vessels leading to a particular part of the body. This prevents the tissue in that part of the body, for example, a tumor, from receiving necessary oxygen and nutrients and inhibits growth of the tissue. The particles may also be administered with a diagnostic or therapeutic agent, allowing the agent to be trapped within or without of the effected tissue for brief periods of time.
European patent application 256,293 to Mitsubishi discloses water-insoluble, crosslinked, polyvinyl alcohol particles in the shape of spheres having an average particle size from 20 to 1,000 micrometers. The particles are produced by dispersing a solution of polyvinyl alcohol and a salt in an organic solvent, such as a hydrocarbon, to form a gel which is then reacted with a crosslinking agent, such as a dialdehyde, diepoxide, glycidyl ether, and epihalohydrin. Suitable salts are sodium chloride, sodium sulfate or any other salt capable of coagulating and precipitating polyvinyl alcohol. A dispersion stabilizer, such as a cellulose or sorbitan derivative, may be added to the reaction mixture. Mitsubishi further discloses that the crosslinked polyvinyl alcohol particles are suitable for packing materials in chromatography.
European patent application 555,980 to Nisshinbo discloses crosslinked, spherical particles of water-soluble polymers, having a particle size from 0.1 to 30 micrometers. Specific polymers disclosed are sodium alginate, dextran, dextran sulfate sodium, carragheenan, agarose, agar, gelatin, pectin, water-soluble cellulose derivatives, such as carboxymethylcellulose sodium. The polymer particles also contain an oligosaccharide or polyhydric alcohol, such as sucrose, which is necessary to provide the particles with a spherical shape. Specific oligosaccharides disclosed are mannose, sucrose, cellobiose and raffinose; specific polyhydric alcohols are polyethylene glycol or erythritol. The Nisshinbo particles are useful as additives and binders because of their water-retaining and lubricating properties.
The polymeric particles of Nisshinbo are made by preparing an aqueous solution of the water-soluble polymer and an oligosaccharide or polyhydric alcohol. This solution is then spray-dried to form spherical particles. Nisshinbo discloses that it is not possible to obtain spherical particles through spray drying techniques without the addition of an oligosaccharide or polyhydric alcohol. The spray dried particles are then crosslinked. Specific covalent crosslinking agents disclosed are divinyl compounds or bisepoxide, while specifically disclosed ionic crosslinking agents are calcium chloride and other divalent metal salts.
U.S. Pat. No. 4,716,154 to Malson, et al. (hereinafter "Malson") discloses a transparent, homogeneous, crosslinked hyaluronic acid gel which is a clear optical mass useful for replacement of vitreous humor in individuals with retinal detachment. The gel may contain other polysaccharides in additional to hyaluronic acid. The gel is administered by injection through a 0.9 millimeter needle tip.
The process by which the gel of Malson is made involves dissolving hyaluronic acid and a crosslinking agent in an alkaline medium, preferably at an elevated temperature of about 50.degree. C. The resulting gel must be washed to remove unreacted crosslinking agent. The preferred crosslinkers disclosed are di- or polyfunctional epoxides.
U.S. Pat. No. 5,603,956 to Mateescu, et al. (hereinafter "Mateescu") discloses crosslinked polymer particles of amylose having a size of about 0.5 to about 5.0 micrometers which form agglomerates of approximately 25-700 micrometers. The polymers are crosslinked solely through .alpha.(1.fwdarw.4) linkages.
The Mateescu particles are formed by direct compression of an admixture of a drug with the crosslinked amylose polymer and an amount of .alpha.-amylase enzyme. The crosslinked amylose polymer is formed by swelling amylose in an alkaline medium in a planetary mixer, with homogenization, followed by addition of the crosslinker with moderate heating of between 40-70.degree. C.
The polymers are useful for the slow release of drugs. The .alpha.-amylase present in the particles breaks down the .alpha.(1.fwdarw.4) linkages, releasing the drug and degrading the polymer.
U.S. Pat. No. 5,371,208 to Kozulic discloses electrophoresis gels having a very low polymer concentration and improved optical properties. The gels are formed by reacting a hydroxyl group containing polymer with a crosslinker that is capable of forming ether linkages, such as bis-epoxides, in an aqueous medium at a basic pH. Because the process is performed in water, hydrolysis of the reactive groups present in the crosslinker is an unavoidable side reaction.
U.S. Pat. No. 5,041,292 to Feijen discloses drug delivery system containing a drug and a biodegradable hydrogel matrix, formed by linking a polysaccharide and a protein with a crosslinking agent. The Feijen process involves dissolving the polysaccharide, protein, and crosslinking agent in an aqueous medium. The crosslinked particles are then loaded with the desired drug. The hydrogel may be shaped into many forms, including microspheres which may be from less than 100 nanometers to over 7 micrometers in diameter. Feijen discloses that the size may be varied in order to place the gels in the capillary bed of the lungs, the liver and spleen through phagocytosis of small particles, and in the extracellular tissue.
The particles formed by Feijen are maintained by mechanical agitation prior to crosslinking, and once formed are stabilized by heat, which is only possible in the presence of the additional protein component. Thus, the size and shape of the particles are controlled solely by the mechanical force of the system.
Thus, there is a need for aqueous dispersions of water-swellable polymer particles of a relatively narrow particle size distribution with defined physical characteristics, for a process for preparing such dispersions, and for recovery of particles in any desired quantity at reasonable cost.